Assessment of Mendelian and risk-factor genes in Alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening.

PURPOSE: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD). METHODS: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92). RESULTS: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees. CONCLUSION: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure.

Outcome of psychogenic non-epileptic seizures following diagnosis in the epilepsy monitoring unit.

Objective: To study the outcome of patients with psychogenic non-epileptic seizures (PNES) after their diagnosis in the epilepsy monitoring unit (EMU). Methods: Patients diagnosed in our EMU with definite PNES between January 2009 and May 2023 were contacted by phone, and those who agreed to participate were asked a set of predetermined questions. Comparative analyses were carried out on several variables before and after diagnosis: number of participants with daily PNES, number of visits to the emergency department, number of participants who consulted their general practitioner or a neurologist outside of a scheduled follow-up, number of participants who took antiseizure medications (ASMs) or psychotropic drugs, and employment status. Results: Out of the 103 patients with a definite diagnosis of PNES, 61 patients (79% female) accepted to participate in our study. The median age at PNES onset was 35 years, and the median delay to diagnosis was 3 years. Almost two-thirds (62%) were receiving ASMs and 40% psychotropic drugs. The mean stay at the EMU was 5 days. PNES diagnosis was explained to almost all patients (97%) by the end of their EMU stay and was well-accepted by most (89%). When contacted, 46% of participants no longer had PNES; 32% mentioned that their PNES had ceased immediately upon communication of the diagnosis. The median follow-up duration was 51 months. Fewer patients had daily seizures after the diagnosis (18 vs. 38%; p < 0.0455). Similarly, the median number of emergency department visits was significantly lower (0 vs. 2; p < 0.001). Only 17 patients consulted their general practitioner (vs. 40, p < 0.001) and 20 a neurologist (vs. 55, p < 0.001) after a PNES attack outside of a scheduled follow-up. The use of ASMs was also significantly reduced from 70 to 33% (p < 0.01), with only one still taking an ASM for its antiseizure properties. Significantly more participants were working at last follow-up than at PNES diagnosis (49 vs. 25%; p < 0.001). Conclusion: Our study revealed a relatively favorable long-term outcome of definite PNES diagnosed in the EMU that translated in significant reductions in PNES frequency, health care utilization and ASM use, as well as a significant increase in employment rate.